The atrial natriuretic peptide and cGMP: Novel activators of the heat shock response in rat livers

Abstract

Preischemic treatment with atrial natriuretic peptide (ANP) attenuates ischemia-reperfusion injury of the rat liver via cyclic guanosine monophosphate (cGMP). The attenuated activation of nuclear factor B (NF-B) seems to contribute to this effect. The aim of this study was to determine whether heat shock proteins are involved in these molecular pathways. Livers of male Sprague-Dawley rats were continuously perfused with Krebs-Henseleit (KH) buffer with or without ANP or 8-Br-cGMP. In different experiments livers were perfused with or without ANP for 20 minutes, kept in cold storage solution for 24 hours, and reperfused. Activation of heat shock transcription factor (HSF) (by electrophoretic mobility shift assay), heat shock protein 70 (HSP70), and glyceraldehyde phosphate dehydrogenase T he "heat shock response" is elicited by a variety of stimuli, including thermal, chemical, and physical stress, as well as short-term ischemia. All organisms respond to such detrimental environmental factors by induction of a group of protective proteins termed heat shock proteins (HSP) (see elsewhere for reviews 1-4 ). The HSPs are subdivided into multimember families based on the molecular weights of the proteins encoded (HSP90, HSP70, HSP60, and the small HSP family), of which HSP70 is one of the most extensively studied in mammalian cells. 2 Studies have revealed that HSPs, in particular HSP70, not only confer thermotolerance, but also protect against oxygen radical toxicity and seem to play an important role in the protection against ischemia reperfusion injury (IRPI). 3,4 Both ischemic 5 or heat shock preconditioning 6-8 induce HSP70 in the liver and the induced HSP70 may contribute to the attenuation of IRPI. This is supported by findings that overexpression of HSP70 in transgenic mice increases the resistance of the heart to ischemic injury. 9,10 HSPs are regulated primarily by changes in gene transcription controlled by a transcription factor termed heat shock factor (HSF). 11,12 The activation process of HSF appears to involve HSF oligomerization from a monomeric to a trimeric state and is associated with HSF hyperphosphorylation. 13 Activated HSF binds to a DNA consensus sequence in the HSP70 promotor termed the heat shock element, 14 leading to the transcription of the HSP70 gene.HSPs seem to protect cells by facilitating the folding of nascent proteins and renaturation or refolding of partially denatured or unfolded proteins. 15 In addition, HSPs can also restrict inflammatory response. Several reports have shown the capacity of HSPs to inhibit the translocation of the proinflammatory transcription factor NF-B and the subsequent expression of inflammatory enzymes 16 and cytokines, such as tumor necrosis factor ␣ (TNF-␣). 1,[17][18][19][20][21] Recently we could show that hormonal preconditioning of livers with the atrial natriuretic peptide (ANP) attenuates reperfusion injury after both warm 22 and cold 23 ischemia of rat livers. The hepatoprotective action of this cardiovascular hormone is mediated via its guanylat...

Atrial natriuretic peptide induces cell death in human hepatoblastoma (HepG2) through the involvement of NADPH oxidase

“…This effect is not in contrast with data showing an ANP cytoprotective action in liver cells subjected to ischemiareperfusion injury, 6 because the spectrum of biological actions of ANP appears to follow different pathways depending on cell phenotype. 7,8 For example, cells which are known to undergo phenotypic modulation, such as those in 'in vivo' atheromatous lesions and cancerous cells such as HepG2, are highly sensitive to ANP, 8,9 because they express a high number of NPR-C receptors.…”

Protective effect of doxorubicin induced heat shock protein 72 on cold preservation injury of rat livers

“…In recent years, preconditioning has been used to prolong hepatic cold ischemia [6,[36][37][38] . The liver graft was subjected to an acute sublethal stress and this preconditioning could offer resistance to subsequent lethal injury by inducing the expression of heat shock proteins (HSPs).…”

Sildenafil Reduces Neuroinflammation and Restores Spatial Learning in Rats with Hepatic Encephalopathy. Underlying Mechanisms

“…cGMP may enhance activation of NF-kB through a noncanonical pathway involving phosphorylation of NF-kB proteins by PKG [35]. However, cGMP may also reduce activation of NF-kB [36] by a mechanism involving cGMP-mediated activation of heat shock transcription factor (HSF), resulting in elevated HSP70 protein and enhanced binding of HSP70 to IkB, the natural inhibitor of NF-kB translocation to the nucleus and activation [37]. Sildenafil would reduce IL-1β levels by increasing cGMP which may reduce transcriptional activity of NF-kB or IL-1β mRNA stability by mechanisms like those discussed above.…”